Interventional drug delivery system and associated methods

ABSTRACT

A delivery system for local drug delivery to a target site of internal body tissue is provided. The delivery system comprises a source electrode adapted to be positioned proximate to a target site of internal body tissue. A counter electrode is in electrical communication with the source electrode, and is configured to cooperate with the source electrode to form a localized electric field proximate to the target site. A reservoir is configured to be disposed such that the reservoir is capable of interacting with the localized electric field. The reservoir is configured to carry a cargo capable of being delivered to the target site when exposed to the localized electric field. Associated methods are also provided.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This disclosure was partially made with U.S. Government support undercontract number CHE-9876674 awarded by the United States NationalScience Foundation and Technology Center. The U.S. Government may havecertain rights in the disclosure.

BACKGROUND

1. Field of the Invention

Embodiments of the present invention relate to an interventional drugdelivery system, and more particularly, to a system for facilitatingdelivery of various cargos, such as, for example, therapeutic agents, totarget sites of internal body tissue in vivo, and methods associatedtherewith, wherein the system implements an electric field to drivecargo through tissue as in iontophoretic approaches.

2. Description of Related Art

Many techniques exist for the delivery of drugs and therapeutic agentsto the body. Traditional delivery methods include, for example, oraladministration, topical administration, intravenous administration, andintramuscular, intradermal, and subcutaneous injections. With theexception of topical administration which permits more localizeddelivery of therapeutic agents to particular area of the body, theaforementioned drug delivery methods generally result in systemicdelivery of the therapeutic agent throughout the body. Accordingly,these delivery methods are not optimal for localized targeting of drugsand therapeutic agents to specific internal body tissues.

As a result, other methods, such as endovascular medical devices,Natural Orifice Translumenal Endoscopic Surgery (NOTES)-based devices,and iontophoresis, have been developed to provide localized targeting oftherapeutic agents to a particular internal body tissue. Iontophoresisis a form of drug delivery that uses electrical current to enhance themovement of charged molecules across or through tissue. Iontophoresis isusually defined as a non-invasive method of propelling highconcentrations of a charged substance, normally therapeutic orbioactive-agents, transdermally by repulsive electromotive force using asmall electrical charge applied to an iontophoretic chamber containing asimilarly charged active agent and its vehicle. In some instances, oneor two chambers are filled with a solution containing an activeingredient and its solvent, termed the vehicle. The positively chargedchamber (anode) repels a positively charged chemical, while thenegatively charged chamber (cathode) repels a negatively chargedchemical into the skin or other tissue. Unlike traditional transdermaladministration methods that involve passive absorption of a therapeuticagent, iontophoresis relies on active transportation within an electricfield. In the presence of an electric field, electromigration andelectroosmosis are the dominant forces in mass transport. As an example,iontophoresis has been used to treat the dilated vessel in percutaneoustransluminal coronary angioplasty (PTCA), and thus limit or preventrestenosis. In PTCA, catheters are inserted into the cardiovascularsystem under local anesthesia and an expandable balloon portion is theninflated to compress the atherosclerosis and dilate the lumen of theartery.

The delivery of drugs or therapeutic agents by iontophoresis avoidsfirst-pass drug metabolism, a significant disadvantage associated withoral administration of therapeutic agents. When a drug is taken orallyand absorbed from the digestive tract into the blood stream, the bloodcontaining the drug first passes through the liver before entering thevasculature where it will be delivered to the tissue to be treated. Alarge portion of an orally ingested drug, however, may be metabolicallyinactivated before it has a chance to exert its pharmacological effecton the body. Furthermore it may be desirable to avoid systematicdelivery all together in order to allow high doses locally whileavoiding potential side effects elsewhere, wherein local delivery isdesirable for localized conditions. Existing medical device technologiesthat enable localized placement of therapeutics fail to provide theopportunity to embed/secure therapeutics in the tissue(s) of interest.

Accordingly, it would be desirable to provide an improved system andmethod for selectively and locally targeting delivery of various drugsand therapeutic agents to an internal body tissue, and fixing suchcargos in the tissue(s) of interest in vivo.

SUMMARY

The above and other needs are met by aspects of the present inventionwhich provide, in one instance, a delivery system, and in particular, adelivery system for local drug delivery to a target site of internalbody tissue. The delivery system comprises a source electrode adapted tobe positioned proximate to a target site of internal body tissue. Acounter electrode is in electrical communication with the sourceelectrode. The counter electrode is configured to cooperate with thesource electrode to form a localized electric field proximate to thetarget site. An electrode deployment device may be used and isconfigured to insert at least one of the source electrode and thecounter electrode proximate to the target site of internal body tissuein vivo. A reservoir is capable of interacting with the localizedelectric field. The reservoir is configured to carry a cargo capable ofbeing delivered to the target site when exposed to the localizedelectric field formed between the source electrode and the counterelectrode. In some aspects, the drug reservoir is capable of beingremotely filled with the cargo.

Another aspect provides a method for delivering a cargo to a target siteof internal body tissue. Such a method comprises disposing a sourceelectrode proximate to a target site of internal body tissue in vivousing an electrode deployment device, and disposing a counter electrodein electrical communication with the source electrode, wherein thecounter electrode is configured to cooperate with the source electrodeto form a localized electric field proximate to the target site. Themethod further comprises disposing a reservoir such that the reservoiris capable of interacting with the localized electric field. Thereservoir is configured to carry a cargo capable of being delivered tothe target site when exposed to the localized electric field formedbetween the source electrode and the counter electrode. In some aspects,the drug reservoir is capable of being remotely filled with the cargo.The method further comprises applying a voltage potential across thesource and counter electrodes to form an electric field, therebydelivering at least a portion of the cargo to the target site.

Yet another aspect provides a method of treating a target site ofinternal body tissue. Such a method comprises delivering a therapeuticagent to a body cavity of a patient for storage thereof. The methodfurther comprises positioning a first electrode proximate to a targetsite of body tissue, and positioning a second electrode such that thesecond electrode is in electrical communication with the firstelectrode. The method further comprises applying a voltage potentialacross the first and second electrodes to drive the therapeutic agentfrom the body cavity to the target site.

As such, embodiments of the present invention are provided to enablehighly targeted and efficient delivery of various cargos topredetermined target sites. In this regard, aspects of the presentinvention provide significant advantages as otherwise detailed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to assist the understanding of embodiments of the invention,reference will now be made to the appended drawings, which are notnecessarily drawn to scale. The drawing is exemplary only, and shouldnot be construed as limiting the invention.

FIGS. 1A-1G are schematic drawings of various embodiments of a deliverysystem having a source electrode and counter electrode configured tocooperate to form an electric field for delivering a cargo, according toone embodiment of the present disclosure;

FIG. 2 is a partial view of a delivery system having a source electrodewith an array of probes, according to an alternative embodiment of thepresent disclosure;

FIG. 3 is a partial view of a delivery system having a source electrodewith an array of probes, according to yet another embodiment of thepresent disclosure;

FIG. 4 is a partial view of a delivery system according to oneembodiment of the present disclosure, illustrating a source electrodehaving a plurality of insulating members engaged therewith;

FIG. 5 is a partial view of a delivery system disposed within a tissuelumen, the delivery system having a plurality of independentlycontrolled source electrodes and a plurality of insulating membersconfigured to provide controlled delivery zones for specific targetingof target sites of the tissue lumen, according to one embodiment of thepresent disclosure;

FIG. 6 is a partial view of a delivery system employing a catheterdevice for positioning of a source electrode, wherein the deliverysystem includes a plurality of independently controlled sourceelectrodes and a plurality of insulating members configured to providecontrolled delivery zones for specific targeting of target sites,according to one embodiment of the present disclosure;

FIG. 7 is a partial view of a delivery system having a source electrodeencapsulated by a polymer matrix reservoir having a cargo containedtherein, according to one embodiment of the present disclosure;

FIGS. 8A and 8B are partial views of a delivery system having a sourceelectrode with at least one insulating member engaged therewith, thesource electrode and at least one insulating member being encapsulatedby a polymer matrix reservoir having a cargo contained therein;

FIG. 9 is a partial view of a delivery system having a plurality ofindependently controlled source electrodes and a plurality of insulatingmembers arranged to provide controlled delivery zones, wherein thesource electrodes and the insulating members are encapsulated in apolymer matrix, according to one embodiment of the present disclosure;

FIG. 10 is a partial view of a delivery system having a source electrodeserially disposed between a pair of expandable members configured toocclude a target site, wherein the expandable members are in a relaxedstate, according to one embodiment of the present disclosure;

FIG. 11 is a partial view of the delivery system of FIG. 10,illustrating the expandable members in an expanded state so as toocclude the target site such that delivery of a cargo is limitedthereto;

FIG. 12 is a partial view of a delivery system having a source electrodecomprising a hollow tube needle member configured to deliver a cargo toa target site of internal body tissue, according to one embodiment ofthe present disclosure;

FIGS. 13A and 13B are partial views of a delivery system having acounter electrode positioned at various orientations with respect to thesource electrode so as to target delivery of a cargo to a target site topredetermined in vivo locations;

FIG. 14 is a partial view of a delivery system having a coolant deviceextending about a counter electrode to provide cooling thereto, thecoolant device having a membrane portion disposed about the counterelectrode, according to one embodiment of the present disclosure;

FIG. 15 is a partial view of a delivery system having a coolant deviceextending about a counter electrode to provide cooling thereto, whereinthe counter electrode is disposed between an insulating member and amembrane portion of the coolant device, according to one embodiment ofthe present disclosure;

FIG. 16 is a partial view of a delivery system having a coolant deviceextending about a counter electrode to provide cooling thereto, thecoolant device having an aperture disposed at a distal end thereof forpermitting a coolant substance to exit therefrom;

FIGS. 17A and 17B are images illustrating an experimental implementationof a delivery system in accordance with one aspect of the presentdisclosure;

FIGS. 18A and 18B are images illustrating an experimental implementationof a delivery system in accordance with another aspect of the presentdisclosure;

FIGS. 19A-19C are images illustrating an experimental implementation ofa delivery system in accordance with yet another aspect of the presentdisclosure;

FIGS. 20A and 20B are images illustrating an experimental implementationof a delivery system in accordance with still another aspect of thepresent disclosure;

FIG. 21 is an image illustrating an experimental implementation of adelivery system in accordance with another aspect of the presentdisclosure;

FIG. 22 is an image illustrating an experimental implementation of adelivery system in accordance with still yet another aspect of thepresent disclosure;

FIGS. 23A and 23B are images illustrating an experimental implementationof a delivery system in accordance with one aspect of the presentdisclosure;

FIGS. 24A and 24B are images illustrating an experimental implementationof a delivery system in accordance with yet another aspect of thepresent disclosure;

FIG. 25 is an image illustrating an experimental implementation of adelivery system in accordance with one aspect of the present disclosure;

FIGS. 26A and 26B are images illustrating an experimental implementationof a delivery system in accordance with yet another aspect of thepresent disclosure;

FIG. 27 is an image illustrating an experimental implementation of adelivery system in accordance with one aspect of the present disclosure;

FIGS. 28A and 28B are images illustrating an experimental implementationof a delivery system in accordance with one aspect of the presentdisclosure;

FIG. 29 is an image illustrating an experimental implementation of adelivery system in accordance with another aspect of the presentdisclosure;

FIGS. 30A-30C are images illustrating an experimental implementation ofa delivery system in accordance with another aspect of the presentdisclosure;

FIGS. 31A and 31B are images illustrating an experimental implementationof a delivery system in accordance with one aspect of the presentdisclosure;

FIG. 32A illustrates an experimental implementation of a delivery systemin accordance with one aspect of the present disclosure;

FIG. 32B shows results of an evaluation of the experimentalimplementation of FIG. 32A according to one aspect of the presentdisclosure;

FIGS. 33A-33D depict various perspective views of a delivery system inaccordance with another aspect of the present disclosure;

FIG. 34 shows experimental results of an evaluation of an experimentalimplementation according to one aspect of the present disclosure;

FIG. 35 illustrates experimental results of an evaluation of anexperimental implementation according to one aspect of the presentdisclosure;

FIG. 36 is an image illustrating an experimental implementation of adelivery system in accordance with an additional aspect of the presentdisclosure; and

FIG. 37 depicts exemplary dimensions of an experimental implementationof a delivery system in accordance with one aspect of the presentdisclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Embodiments of the present invention now will be described more fullyhereinafter with reference to the accompanying drawings. The inventionmay be embodied in many different forms and should not be construed aslimited to the embodiments set forth herein; rather, these embodimentsare provided so that this disclosure will satisfy applicable legalrequirements. Like numbers refer to like elements throughout.

Embodiments of the present invention are directed to systems and methodsfor delivering treatment or therapeutic agents (otherwise referred toherein as “cargo”) to specific locations, including intracellularlocations in a safe and effective manner. Such systems may deliver theagents to a diseased site in effective amounts without endangeringnormal tissues or cells and thus reduce or prevent the occurrence ofundesirable side effects. Further, such systems may electrically enhancethe local delivery of treatment agents into the wall tissues or cells ofthe living body. These systems are designed to target certain tissue andcell locations and deliver the treatment agents directly to thoselocations, while minimizing any effects on non-targeted tissues andcells. In particular, embodiments of the present invention relate tosystems which provide an electrical driving force that can increase therate of migration of drugs and other therapeutic agents out of areservoir into body tissues and cells using iontophoresis and otherapproaches.

More particularly, embodiments of the present invention rely on thetransport of charged and uncharged species under the influence of alocalized electric field generated at the site of interest. The overalltransport of charged and uncharged species is based upon threecharacteristic driving forces, which includes passive diffusion,electroosmosis, and electromigration. Passive diffusion involves themovement of a chemical species from a region of high concentration to anarea of low concentration. Electroosmosis is the movement of a solutespecies via a solvent flow accompanied by the movement of an extraneouscharged species. Electroosmosis encompasses the solvent flow referred toas hydrokinesis. Electromigration is the movement of a charged speciesthrough an applied electric field to an electrode of opposite polarity.Transport of a neutrally charged species is driven by passive diffusionand electroosmosis only, whereas all transport modalities, passivediffusion, electroosmosis, and electromigration contribute to the fluxof a charged species.

In this regard, embodiments of the present invention may provide aninterventional drug delivery system and methods for localized deliveryof therapeutic agents to internal locations in the human body using acontrolled electrical field. The systems may be constructed to deliverthe agents specifically to the site of interest, improving penetrationof the agent while limiting effect upon non-targeted tissue. Embodimentsof the present invention may be fashioned to deliver the agents viaintravascular, intraperitoneal, minimally invasive surgery, and naturalorifice transluminal endoscopic surgery (NOTES) modalities. The actionof the electric field may be controlled through a programmable powersupply or a function generator. By using various electrode designs andplacement configurations, highly localized and focused delivery of cargoto the tissue of interest may be achieved. The overall controlledrelease characteristics of the delivery system may be dependent upon thecharge, size, conductivity, concentration, and pK_(a) of the chemicalspecies and nanoparticles, pH of the surrounding environment, resistanceof the site of interest, current and voltage applied, electrode designand amount of extraneous ions at site of interest.

Embodiments of the present invention may be implemented in the deliveryof therapeutic agents for such diverse areas as oncology, pulmonary,gastrointestinal (GI), and neurology applications. Embodiments of thepresent invention find application in the field of interventionaloncology for the treatment of various cancers, which may include, forexample, pancreatic cancers, lung cancer, esophageal cancers, bladdercancers, colorectal cancers, liver cancers, hepatic metastases, bileduct cancers, renal cancers, cervical cancers, prostate cancers, ovariancancer, thyroid cancers, uterine cancers, and leukemia. In particular,accessing bone marrow tissue may be advantageous. Other applications maycover pulmonary diseases, neurological disorders as well ascardiovascular applications.

In some instances, embodiments of the present invention may employ anapproach using iontophoresis. As used herein, the term “iontophoresis”means the migration of ionizable molecules through a medium driven by anapplied low level electrical potential. This electrically mediatedmovement of molecules into tissues is superimposed upon concentrationgradient dependent diffusion processes. If the medium or tissue throughwhich the molecules travel also carries a charge, some electro-osmoticflow occurs. However, generally, the rate of migration of molecules witha net negative charge towards the positive electrode and vice versa isdetermined by the net charge on the moving molecules and the appliedelectrical potential. The driving force may also be considered aselectrostatic repulsion. Iontophoresis usually requires relatively lowconstant DC current in the range of from about 2-5 mA. The appliedpotential for iontophoresis will depend upon number of factors, such asthe electrode configuration and position on the tissue and the natureand charge characteristics of the molecules to be delivered.

The present invention relates to the delivery of cargo including, butnot limited to, therapeutic agents such as drug molecules, proteins,peptides, antibodies, antibody scaffolds or fragments of antibodies,nucleotides, contrast agents and dyes (including radiolabels,fluorophores and chelated magnetic species), liposomes, micelles,nanoparticles, multi-molecular aggregates (such as, for example,albumin/paclitaxel or Abraxane™) and combinations thereof, with orwithout cargo and/or targeting capabilities. Small molecules may includechemotherapeutic agents such as alkylating agents, anti-metabolites,plant alkaloids and terpenoids, vinca alkaloids, podophyllotoxin,taxanes, topoisomerase inhibitors, and antitumor antibiotics, as well asanalgesics and local anesthetics. Embodiments of the present inventionalso covers the delivery of pro-drugs, small molecules andnanoparticles, in some instances having neutral charge before delivery,that may be subsequently charged or triggered to release cargo underphysiological conditions.

Furthermore, the cargo may include small ionic molecules, nucleic acids,proteins, therapeutic agents, diagnostic agents, and imaging agents aswell as organic nanoparticles which may encapsulate a wide range oftherapeutic, diagnostic, and imaging agents. The cargo may be configuredto traffic preferentially based on size, shape, charge and surfacefunctionality; and/or controllably release a therapeutic. Such cargosmay include but are not limited to small molecule pharmaceuticals,therapeutic and diagnostic proteins, antibodies, DNA and RNA sequences,imaging agents, and other active pharmaceutical ingredients. Further,such cargo may include active agents which may include, withoutlimitation, analgesics, anti-inflammatory agents (including NSAIDs),anticancer agents, antimetabolites, anthelmintics, anti-arrhythmicagents, antibiotics, anticoagulants, antidepressants, antidiabeticagents, antiepileptics, antihistamines, antihypertensive agents,antimuscarinic agents, antimycobacterial agents, antineoplastic agents,immunosuppressants, antithyroid agents, antiviral agents, anxiolyticsedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptorblocking agents, blood products and substitutes, cardiac inotropicagents, contrast media, corticosteroids, cough suppressants(expectorants and mucolytics), diagnostic agents, diagnostic imagingagents, diuretics, dopaminergics (antiparkinsonian agents),haemostatics, immunological agents, therapeutic proteins, enzymes, lipidregulating agents, muscle relaxants, parasympathomimetics, parathyroidcalcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals,sex hormones (including steroids), anti-allergic agents, stimulants andanoretics, sympathomimetics, thyroid agents, vasodilators, xanthines,and antiviral agents. In addition, the cargo may include apolynucleotide. The polynucleotide may be provided as an antisense agentor interfering RNA molecule such as an RNAi or siRNA molecule to disruptor inhibit expression of an encoded protein.

Other cargo may include, without limitation, MR imaging agents, contrastagents, gadolinium chelates, gadolinium-based contrast agents,radiosensitizers, such as, for example, 1,2,4-benzotriazin-3-amine1,4-dioxide (SR 4889) and 1,2,4-benzotriazine-7-amine 1,4-dioxide (WIN59075); platinum coordination complexes such as cisplatin andcarboplatin; anthracenediones, such as mitoxantrone; substituted ureas,such as hydroxyurea; and adrenocortical suppressants, such as mitotaneand aminoglutethimide.

In other embodiments, the cargo may comprise Particle Replication InNon-wetting Templates (PRINT) nanoparticles (sometimes referred to asdevices) such as disclosed, for example, in PCT WO 2005/101466 toDeSimone et al.; PCT WO 2007/024323 to DeSimone et al.; WO 2007/030698to DeSimone et al.; and WO 2007/094829 to DeSimone et al., each of whichis incorporated herein by reference. PRINT is a technology whichproduces monodisperse, shape specific particles which can encapsulate awide variety of cargos including small molecules, biologics, nucleicacids, proteins, imaging agents. Cationically charged PRINTnanoparticles smaller than 1 micron are readily taken up by cells over arelatively short time frame, but penetration of the particles throughoutthe tissue is a longer process. For the delivery of PRINT nanoparticlesthroughout the tissue to be effective, the penetration needs to occurwithin a reasonable operational time frame. As such, the delivery systemmay be used to achieve such penetration by employing iontophoresis, inwhich charged PRINT nanoparticles are driven into body tissue usingrepulsive electromotive forces. The PRINT particles may or may notcontain a therapeutic. In some instances, the particle may be comprisedof PLGA. In addition, the PRINT nanoparticles may be engineered toachieve a certain mission, and design-in handles that permit remotecontrol for externally turning the cargo “on” or switching it “off”. Assuch, the cargo may be manipulated using ultrasound, low-dose radiation,magnetics, light and other suitable mechanisms. The particles may becoated with gold such as, for example, gold nano-shells for thermalablation therapy.

FIGS. 1-15 illustrate various embodiments and aspects of a deliverysystem 100 in accordance with the present invention. In general, thedelivery system is provided for delivering a cargo to, or through, alocalized area of a passageway or other internal body tissue in order totreat the localized area of the passageway or tissue with minimal, ifany, undesirable effect on other body tissue. Such a system may beimplemented intraluminally, through natural orifices, or by minimallyinvasive surgery such that the system may be used in vivo. The deliverysystem 100 may generally include a source electrode, a counterelectrode, a reservoir for carrying a cargo (e.g., a therapeutic agent),and an electrode deployment device.

As described previously, the delivery apparatus 100 which may delivercargo iontophoretically to target sites for localized treatment. Ingeneral, iontophoresis technology uses an electrical potential orcurrent across a target site (e.g., a semipermeable barrier) to driveionic fixatives or drugs (or drive nonionic fixatives or drugs) in anionic solution. Iontophoresis facilitates both transport of the fixativeor drug across the target site and enhances tissue penetration. In theapplication of iontophoresis, two electrodes, a source electrode and acounter electrode (in some instances, the electrodes may be positionedon opposing sides of the target site, though such a configuration orarrangement is not required), are utilized to develop the requiredpotential or current flow. The positioning of the electrodes may beaccomplished using an electrode deployment device 150. The electrodedeployment device 150 may be capable of positioning the sourceelectrode, the counter electrode, and the reservoir such that thetherapeutic agents may be delivered through intravascular,intraperitoneal, and natural orifice transluminal endoscopic surgery(NOTES) modalities. Some embodiments of the present invention may employthe technique of reverse iontophoresis, wherein a small molecule orother substance may be extracted from the surrounding medium. In thismanner, toxic substances or excess cargo materials may be removed fromlocations in vivo.

In some instances, the electrode deployment device 150 may comprise acatheter device to be deployed in vivo using the intravascular route. Inother embodiments, the electrode deployment device 150 may comprise anendoscopic device for deployment via natural orifices in the body. Inother instances, the electrode deployment device 150 may comprise alaparoscopic device for minimally invasive surgical intervention. Inother embodiments, the electrode deployment device 150 may be surgicallyimplanted in a suitable location in vivo, such as, for example, theperitoneal cavity. In yet other instances, the electrode deploymentdevice 150 may implement combinations of two or more of the embodimentslisted above. According to some embodiments, the electrode deploymentdevice 150 may locate the source electrode, counter electrode, and/orreservoir at the target site of interest through use of an imagingsystem.

FIGS. 1-11 illustrate various embodiments of a source electrode 200implemented by the delivery system 100. The repulsive force for drivingthe charged cargo through the target site tissue is generated by placingthe source electrode 200 at or proximate to the target site of interest.The delivery system 100 may include one or more source electrodes 200.By optimizing the placement and geometric profile of the sourceelectrode(s) 200, considerable control may be achieved over thepenetration depth, direction and overall area of delivery of the cargoto the target site. The source electrode(s) 200 may be configured as asingle probe or an array of probes comprised, for example, of thinwires, foil, mesh, pellets, disks, stents, clamps, prongs, clips,needles, hollow tubes or combinations thereof. For example, as shown inFIG. 1, the source electrode 200 may include a mesh arrangement 225 (seealso FIGS. 1B, 1C, and 18B) opposably positioned with respect to acounter electrode 500. In accordance with such an embodiment, in someinstances, the counter electrode 500 may be positioned, for example, onan exterior surface of the pancreas/organ of interest. The sourceelectrode 200 having the mesh arrangement 225 may also be placed on theexterior surface to cover a specific target tissue such as, for example,a tumor, as shown in FIG. 1B.

In another embodiment, the mesh arrangement 225 source electrode 200 maybe configured to encase part or a portion of the target tissue (e.g., aconical mesh encasing the tail of the pancreas, as shown in FIG. 1C). Inother instances, the source electrode 200 may be configured or arrangedas foil or patch electrodes 235, as shown in FIG. 1D, wherein the drugreservoir 300 is coupled to the source electrode 200. The patch sourceelectrode 235 may be configured as clamps or prongs situated at the endof the electrode deployment device 150, such as, for example, anendoscopic or laparoscopic device, as shown in FIG. 2, wherein anintermediary prong 208 may include the patch source electrode 235. Inthis regard, the configuration may be modified to be internally deployedby the electrode deployment device 150, wherein the mesh arrangement 225may be replaced by a stent device 245 (acting as the source electrode200), as shown in FIG. 1E, that is positioned within the pancreatic duct20, while the counter electrode 500 may be positioned within analternate branch of the same duct or, alternatively, the bile duct 25for example, as shown in FIG. 1F. In some instances, the sourceelectrode may include a reservoir 300 coupled or otherwise attachedthereto for holding the cargo to be delivered to the target site. Inthis manner, the reservoir 300 and/or the tissue of interest may be atleast partially disposed between the source electrode 200 and thecounter electrode 500. The source electrode(s) 200 may be fabricatedfrom various materials including, but not restricted to, conductingmetals, such as silver, silver chloride, platinum, aluminum, orconducting polymers such as polypyrrole, polyaniline, or polyacetylene.In some instances, both the source electrode 200 and the counterelectrode 500 may be patch source electrodes 235, which may bepositioned in a side-by-side or otherwise proximally positioned on anorgan, tissue, or other target site, as shown in FIG. 1G. That is, thecargo of the reservoir 300 may penetrate the target site to reach, forexample, a tumor when the voltage potential is applied between thesource electrode 200 and the counter electrode 500. Of course, the patchsource electrodes 235 may be on opposite sides of the organ, tissue, ortarget site, or may be otherwise appropriately configured to deliver thecargo to the target site.

According to some embodiments, the source electrode 200 may include anarray of multi-functional probes, combining imaging and drug deliveryfunctionalities, as illustrated in FIGS. 2 and 3. In this regard, theuse of paramagnetic or radio-opaque materials in the probe body may beused for imaging purposes. In other instances, catheter devices may becapable of simultaneous delivery of imaging agents. According to otherembodiments, the incorporation of a light source and camera may beincorporated into the probe for endoscopic devices. Various combinationsof such imaging and delivery probes may be implemented by the deliverysystem 100. For example, as illustrated in FIG. 2, the intermediaryprong 208 may include the electrode element 204, while the outer prongs210, 212 include imaging devices and/or agents capable of assisting withpositioning of the source electrode 200. With reference to FIG. 3, theelectrode element 204 may be radially surrounded by imaging devices 210or agents, other source electrodes 200 or other probe members, which maybe configured as dependent on the location of the target site within apatient's body.

In some instances, the source electrode 200 may have one or moreinsulating layers or members 250 attached, connected, or otherwiseengaged therewith. The insulating members 250 are provided to conferdirectionality to the transport profile of the cargo 60 with respect tothe target site, as shown in FIG. 4, illustrating the source electrode200 disposed within a tissue lumen 50. That is, the flux of the cargowill be attenuated corresponding to the insulated areas of the sourceelectrode 200. In this regard, a partially insulated source electrode200 may be for control over targeted delivery to specific in vivolocations. That is, by insulating a portion of the source electrodesurface, control over delivery to the tissue or organ systems may beaccomplished in a well defined manner. In this regard, the extent oftransport from the sections of the target site exposed to the unshieldedsections of the source electrode 200 may be greater than that of thetransport from the shielded or insulated region of the source electrode200.

According to some aspects of the present invention, a plurality ofsource electrodes 200 may be provided, wherein each source electrode 200is independently controlled with respect to the other source electrodes200. In this manner, the delivery system 100 may be manipulated totarget various sites for delivery of the cargo 60, as shown in FIG. 5,illustrating the source electrodes 200 disposed within a tissue lumen50. That is, by allowing independent control over parameters foriontophoretic delivery such as current, voltage and time, variabledelivery zones may be created at distinct sites within the same tissuelumen. In addition, the source electrodes 200 may terminate at variouslengths to further provide control over deliver of the cargo to thetarget site(s). Furthermore, in some instances, the plurality of sourceelectrodes 200 may have the insulating members 250 disposed therebetweenand thereabout to also specifically designate delivery regions 260 fordelivery of the cargo 60 to the target site(s). According to analternative embodiment, the source electrodes may be disposed within theelectrode deployment device 150, such as, for example, a catheter device350, as illustrated in FIG. 6. The catheter device 350 may be comprisedof a perforated polymer sheath 352. That is, the catheter device 350 mayhave a plurality of perforations 354 defined thereby such that the cargo60 may exit the catheter device 350. In one particular embodiment, thesource electrodes 200 terminate at different lengths and may beindependently powered such that the probes are capable of being variablycontrolled. The source electrodes 200 may include the insulating members250 disposed about and between the source electrodes 200 so as to formcargo delivery zones substantially aligned with the perforations 354 ofthe catheter device 350. In this regard, the cargo 60 may be fed throughthe catheter device 350 proximate to the target site at the terminalportion of the catheter device 350, where the cargo 60 may be drawntherefrom due to the electrical field applied across the sourceelectrode 200 and the counter electrode.

Referring to FIG. 7, in some instances, the source electrode 200 (and/orthe counter electrode) may be encapsulated in a gelatinous solid, suchas, for example, a soft polymer matrix 280, that prevents injury fromthe insertion and extraction of the source electrode 200 (and/or thecounter electrode). The polymer matrix 280 may also serve as a cargoreservoir 300 from where the therapeutic agent(s) may be mobilized. Thatis, the cargo 60 may be incorporated in the polymer matrix 280 suchthat, upon actuation of the electric field, the cargo 60 may diffuse outof the polymer matrix 280 and be delivered to the target site. FIGS. 8Aand 8B illustrate the source electrode 200 having one or more insulatingmembers 250 disposed thereabout such that both the source electrode 200and the insulating members 250 are encapsulated in the polymer matrix280. FIG. 8A shows a single insulating member 250 disposedlongitudinally along the source electrode 200 such that the cargo 60 maybe directed toward the target site. FIG. 8B shows a plurality ofinsulating members 250 engaged with the source electrode 200 such thatvarious cargo delivery regions or zones are defined for delivering thecargo 60 to specific areas of the target site. In this regard, there maybe a region or regions 290 of depleted cargo within the polymer matrix280 and a normal region or regions 295 at some duration after actuationof the electric field to drive the cargo 60 toward the target site.

FIG. 9 illustrates an embodiment of the delivery system 100 similar tothat of FIG. 5, wherein a plurality of independently controlled sourceelectrodes 200 may be provided such that various target sites and/orregions may be targeted for delivery. As described previously, thelength at which the source electrodes 200 terminate may alter and theinsulating members 250 may be provided to further control delivery ofthe cargo 60. In some instances, as shown in FIG. 9, the sourceelectrodes 200 and insulating members 250 may be encapsulated in agelatinous solid such as, for example, the polymer matrix 280 carryingthe cargo 60 therewith. In this manner, there may be a region 290 ofdepleted cargo within the polymer matrix 280 and a normal region 295 atsome duration after actuation of the electric field to drive the cargo60 toward the target site.

In one embodiment, as illustrated in FIGS. 10 and 11, a catheter device,such as, for example, a balloon catheter 400 having a pair of expandablemembers 402 may be used to deliver the cargo 60 to the target site. Thesource electrode 200 may be serially disposed between the pair ofexpandable members 402, which are configured to occlude a target site.In this regard, the expandable members 402 may be used to enclose orocclude an intraluminal area before and/or after the source electrode200, to limit the delivery of the cargo (e.g., therapeutic agent) to thearea of interest. That is, the expandable members 402 may be in arelaxed state (FIG. 10) during positioning of the catheter and/or sourceelectrode 200 proximate to the target site. Thereafter, the expandablemembers 402 may be inflated to an expanded state (FIG. 11) so as tocontact a duct or other passageway 410 to enclose the target site suchthat the cargo delivery is isolated to the target site, thereby limitingexposure of healthy tissue to the cargo materials. In one embodiment,the delivery system 100 may include inflatable members 402, asschematically shown in FIGS. 10 and 11, which illustrate the distal endof the catheter device 400 with the expandable member 402 in its relaxedand inflated/expanded states, respectively. The catheter device 400 mayinclude a guide wire for positioning the catheter device 400 near thetarget site. The term catheter as used in the present application isintended to broadly include any medical device designed for insertioninto a body passageway to permit injection or withdrawal of fluids, tokeep a passage open or for any other purpose. In other instances, anarea to be treated may be occluded by blocking or damming an area usinga balloon or a polymer cap or fibers (not shown).

With reference to FIG. 12, in some embodiments of the present invention,placement of the cargo, such as the PRINT nanoparticles, may be achievedby using a hollow tube needle member 500 having an iontophoretic tip tofacilitate distribution of the particles into the surrounding targetsite (tissue). In such embodiments, the needle tip may represent thesource electrode 200, while the counter electrode is positionedinternally or external to the body so as to create a voltage potentialwhen a power supply is energized, as described previously with respectto iontophoretic techniques. Such a technique may be used for diseasestates including cancer (brain, prostate, colon, others), inflammation,damaged tissue ‘rescue’ situations (e.g. cardio/neuro/peripheralvascular), ocular diseases, rhinitis, and other applications.Furthermore, the hollow tube portion of the needle member 500 may serveas a reservoir for the cargo, wherein the needle member 500 may beconnected to a port member (not shown) located externally such that thereservoir may be filled and/or refilled externally.

Referring to FIGS. 13A, 13B, 14, 15, and 16, one or more counterelectrodes 500 may be provided with the delivery system 100, wherein thecounter electrode 500 consists of a probe of opposite polarity to thatof the source electrode 200 that completes the electrical circuit of thesystem. That is, in using embodiments of the present invention foriontophoretically enhanced drug delivery, a separate electrode ofopposite polarity to the source electrode 200 is used in order togenerate the potential gradient across the artery or other body tissue.In some instances, the counter electrode 500 may be positionedinternally or otherwise external to the body such as on the patient'sbody (usually the skin) and may be attached using any known means, suchas ECG conductive jelly. That is, placement of the source electrode 200and the counter electrode 500 may be altered to fit the tissue locationand disease state to be treated. For example, the source electrode 200and the counter electrode 500 may be placed internally, externally orone internal and one external as long as appropriate electricalconnection can be made. Internally placed electrodes can be proximal ordistal in relation to each other and the tissue.

In some instances, as shown in FIGS. 13A and 13B, the counter electrode500 may be designed to maximize movement of the cargo (e.g., thetherapeutic agent) towards itself and away from the source electrode 200so as to promote distinct and varied delivery zones 550. That is, theposition of the counter electrode 500 may be manipulated to exertcontrol over targeted delivery to specific in vivo locations. Forexample, as shown in the configuration of FIG. 13A, the counterelectrode 500 may be positioned substantially perpendicularly withrespect to the source electrode 200, whereas, as shown in theconfiguration of FIG. 13B, the counter electrode 500 may beconcentrically positioned about the source electrode 200. Suchconfigurations of the counter electrode 500 may lead to highlydirectional transport or broader transport bands, as dependent on theconfiguration and orientation with respect to the source electrode 200.

In some instances, the counter electrode 500 can have an ion selectivemembrane portion 502 for the movement of ions to and from the counterelectrode 500. In some instances, the counter electrode 500 may have acoolant device 510 for use therewith to maintain the temperature of thecounter electrode 500 and to minimize the potential for tissue burns, asillustrated in FIGS. 14-16. The coolant device 510 may be configured toallow a coolant substance 512 to flow at least partially about thecounter electrode 500. In this regard, the membrane portion 502 may bepositioned to prevent ions that may be part of the coolant substance 512from interfering with the cargo, drug, or material to be deposited. Insome embodiments, the coolant device 510 may include a perforatedtubular structure 514 defining an aperture 516 to allow for release ofthe coolant around the counter electrode 500, as shown in FIG. 16. Thecoolant substance 512 may be, for example, water, an electrolytesolution, or gel-like substance that has a high heat capacitance tomaintain cooler temperatures. In addition to performing a coolingfunction, the coolant substance 512 may allow for a continuous flow ofelectrolytes for maximum ion transfer into the tissue, and maintain pHlevels around the counter electrode 500. A gelatinous membrane aroundthe counter electrode 500 may also be utilized, to minimize pH changesoccurring at the conducting surface and tissue interface. In oneparticular embodiment, the counter electrode 500 may be disposed betweenthe insulator member 250 and the membrane portion 502 so as to improvedelivery control of the cargo to the target site.

Embodiments of the present invention further comprise a reservoir (see,for example, FIGS. 1, 6-9, and 12) configured to store or otherwisecarry the cargo such that the cargo may be at least partially disposedbetween the source electrode 200 and the counter electrode 500. In thismanner, the cargo may interact with the electric field formed betweenthe source electrode 200 and the counter electrode 500 so as to bedelivered to the target site. The reservoir can be maintained as asolution, dispersion, emulsion or gelatinous solid, as previouslydescribe with respect to FIGS. 7-9. The reservoir entraps the cargo(e.g., the therapeutic agent) until the application of a physical,chemical, or electrical stimulus. In one embodiment, the cargo reservoirmay be located remotely from the source electrode 200 and may beconnected to the source electrode 200 via a hollow conduit. In anotherembodiment, the reservoir and the source electrode 200 may be designedto be a single assembly. In any instance, it may be possible to refillthe reservoir, either remotely or after every use. Large, medium, andsmall reservoirs may be provided to allow for directionality andconcentration of the cargo (e.g., the therapeutic agent) issued to thetissue of interest.

In one particular embodiment of the present invention, theintraperitoneal cavity may serve as the drug reservoir. In this regard,the peritoneal cavity may be flooded with a cargo or drug of choice inan appropriate buffer. The source and counter electrodes 200, 500 may bepositioned proximate to the target site of the pancreas, such as, forexample, in a pancreatic duct and at an appropriate location orlocations at the exterior of the pancreas near the tumor. Variousarrangements of the source and counter electrodes may be implemented sothat the cargo is positioned to interact with the electric field, uponactuation thereof, to drive the cargo to the target site of thepancreas. That is one, both, or neither of the electrodes may bepositioned substantially within the pancreas. For example, bothelectrodes may be positioned exterior to the pancreas and on oppositesides thereof. In one particular example, one of the electrodes may bearranged as a wire mesh arrangement that can be positioned on andcontact an exterior surface of the pancreas. A current may then beapplied to drive the cargo (e.g., drug or therapeutic agent) from theperitoneal cavity to the pancreas and the site of the tumor. In anotherinstance, the reservoir may be implanted in the intraperitoneal cavitysuch that the reservoir is provided remotely from the source electrode200 and the counter electrode 500.

However, embodiments of the present invention may also be used inassociation with other cavities of the body, wherein at least some ofthese cavities are internal body cavities, while others are not. Forexample, the cargo may be delivered to the cranial cavity (braincancers), the oral cavity (head and neck cancers, thyroid cancers), thethoracic cavity or mediastinum (thymus cancer, esophageal cancers andheart disease), the pleural cavity (lung cancers, cystic fibrosis,pulmonary fibrosis, emphysema, adult respiratory distress syndrome(ARDS), and sarcoidosis), the abdominopelvic cavity or peritoneal cavity(pancreatic cancer, liver cancers and metastases, stomach cancer, smallbowel cancer, genital warts, inflammatory bowel diseases (Crohn'sdisease and ulcerative colitis), renal cancers and metastases, spleniccancers, and Hodgkin's disease), and the pelvic cavity (testicularcancer, prostate cancer, ovarian cancer fallopian tube, cervical cancer,endometrial cancer, uterine cancers, Kaposi's sarcoma, colorectalcancers, and urinary bladder cancer).

In order to apply a voltage potential across the source electrode 200and the counter electrode 500, the source electrode 200 and the counterelectrode 500 are in electrical communication. In this regard, thesource electrode 200 and the counter electrode 500 are connected to apower source (not shown). In some instances, the power source maycomprise a programmable power supply and function generator capable ofgenerating both direct current and pulsed waveforms at various voltagesand for various time intervals. The power source can generate thepotential difference between the source electrode 200 and the counterelectrode 500 necessary to induce electromigration and electroosmosis ofthe cargo (e.g., the therapeutic agent). A function generator allows formanipulation of the wave generated from the power source. Square,triangular, sawtooth, multi-step wave forms may be used to drive adirect current through the source and counter electrodes 200, 500.

As described above, the disclosed iontophoretic techniques may takeeither an inside-out or an outside-in approach in driving the cargotoward the target site of tissue. That is, reverse iontophoretictechniques may be employed in all of the embodiments describedhereinabove, and as described, for example, in Example 8. In thisregard, the source electrode may be disposed exterior to a duct, organ,tissue, or target site, while the counter electrode is positioned withina duct, lumen, organ, etc. such that the cargo is driven from outsidethe target site inwardly toward the target site.

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing description; andit will be apparent to those skilled in the art that variations andmodifications of the present invention can be made without departingfrom the scope or spirit of the invention. Therefore, it is to beunderstood that the invention is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

The following examples are presented by way of illustration, not by wayof limitation.

EXPERIMENTAL Example 1 Delivery of Rhodamine 6G Dye into AgarosePhantoms

A cylindrical tube of 2% (w/v) agarose gel in deionized (D.I.) water wasfabricated as a phantom with an outer diameter (o.d.)=2.5 cm and length˜3-4 cm. A concentric reservoir for holding the dye (o.d=0.8 cm, length˜2 cm) was cored out from the top surface along the longitudinal axis ofthe gel cylinder. Electrodes were fabricated out of aluminum foil (width˜0.5 cm, length ˜15 cm, thickness ˜0.1 cm). A solution of 0.5% Rhodamine6G in D.I. water was used to model the delivery of a small moleculedrug. The dye was filled inside the cored reservoir in the agarosephantom and the source electrode (anode, in this case) was inserted intothe dye reservoir. The other end of the anode was hooked to a DC powersource with an alligator clip. The agarose phantom was immersed in abeaker containing 0.25×PBS solution, as shown in FIG. 17A. The cathode,a second piece of aluminum foil, was placed in the PBS beside theagarose phantom and hooked up to the DC power source. In the negativecontrol, passive diffusion of the dye was allowed without any passage ofcurrent for 10 minutes. In the experimental condition, a constantcurrent of 5 mA (voltage ˜9.5V) was driven through the electrodes forthe same duration (10 minutes). As shown in FIG. 17B, to characterizethe extent of iontophoretic transport, cross-sections of the agarosephantom were taken every 0.5 cm along the length. The radial transportof the dye from the edge of the cored reservoir was quantified. In thenegative control (0 mA) dye was localized to the inner wall of thereservoir, while in the experimental condition (5 mA) the dye spreadradially to the edge of the agarose phantom.

Example 2 Unshielded Electrode Configurations for Control Over TargetedDelivery to Specific In Vivo Locations

Unshielded electrode configurations were developed for demonstratingcontrol over delivery to specific in vivo locations. These includeelectrodes fabricated out of metal wire (silver, silver chloride), metalfoil (silver, platinum, aluminum) and wire mesh (aluminum), as shown inFIGS. 18A and 18B. These are representative examples, and similardesigns can be fabricated with variations in size, material andadditional enhancements or refinements to the basic configuration. Theadvantages of wire and foil electrodes shown FIG. 18A are: simplicityand ease of use, flexibility for insertion into tiny orifices and ducts,precise control over size and potential for miniaturization. Theirprimary limitation is their tendency for hydrolysis of the conductingfluid medium. Silver electrodes are also susceptible to oxidation, whilesilver chloride electrodes can get reduced to metallic. As shown in FIG.18B, wire mesh electrodes can be fabricated either in a stentconfiguration for intra-luminal placement, or as a patch or netconfiguration for placement on the outside surface of an organ or targettissue. Such a configuration may provide greater control over thesurface area of delivery, as well as better heat flow to reduce thepotential for tissue burns. Additionally, these may be fabricated fromconducting polymers or coated with biodegradable polymers to createdesigns that are highly conformable to organ surface characteristics andgeometrical contours.

Example 3 Insulated Electrode Configurations for Control Over TargetedDelivery to Specific In Vivo Locations

An insulated electrode was developed to demonstrate control overtargeted delivery to specific in vivo locations. By insulating a portionof the electrode surface, it is possible to control the delivery to thetissue or organ systems in a well defined fashion. For example, the fluxof drug or particles will be attenuated corresponding to the insulatedareas of the electrode. Aluminum foil was folded into a long rectangularshape of appropriate dimensions (length ˜10 cm, width ˜0.4 cm, thickness˜0.1 cm). Insulating tape (width ˜1 cm) was wrapped around the foil inalternating sections. This insulated electrode was immersed in thecentral reservoir of an agarose phantom (2% agarose w/v in deionizedwater), as shown in FIG. 19A. A solution of 0.5% Rhodamine 6G in D.I.water was used to model the delivery of a small molecule drug. The dyewas filled inside the cored reservoir in the agarose phantom and theinsulated source electrode (anode, in this case) was inserted into thedye reservoir. The agarose phantom was immersed in a beaker containing0.25×PBS solution. A bare aluminum foil electrode served as a cathode,and was placed in the PBS beside the phantom. Both electrodes werehooked to a DC power source with alligator clips. In the negativecontrol, passive diffusion of the dye was allowed without any passage ofcurrent for 10 minutes. In the experimental condition, a constantcurrent of 5 mA (voltage ˜9.5V) was driven through the electrodes forthe same duration (10 minutes). To characterize the extent ofiontophoretic transport, the agarose phantom was sectionedlongitudinally. A difference is seen in the extent of transport from thesections of the phantom exposed to the unshielded sections of theelectrode, as compared to diffusion from the passive control, as shownin FIGS. 19B and 19C, respectively.

Example 4 Electrode Configurations with Built-in Drug Reservoirs

Since it may not be possible to confine the drug to be delivered withina localized cavity or lumen in the target tissue, electrodes withbuilt-in drug reservoirs were developed. Such examples were fabricatedby encapsulating insulated foil electrodes described earlier within anagarose gel matrix. The agarose gel containing the 0.5% Rhodamine 6Gsolution, serving as a model drug, was first poured into a glasstest-tube of diameter 1.2 cm. The insulated electrode was then insertedinto the gel solution. The gel was allowed to solidify, and theelectrode was extracted by breaking the test tube. An agarose gelphantom with a central reservoir of inner diameter ˜1.5 cm was prepared.This electrode was then inserted into the phantom and tested foriontophoretic delivery at a constant current of 5 mA for 10 minutes. Theresults show zones of controlled delivery through the gel that arevisible under short wave UV light, as shown in FIG. 20B. FIG. 20A showsthe electrode having the built-in drug reservoir being at leastpartially depleted of the model drug after completion of the experiment.Similar results were also seen in transport through muscle and fattissue.

Example 5 Delivery of Dye into Muscle Tissue (Chicken Breast)

A soft-gel electrode was fabricated from 2% (w/v) agarose gel containing5% Rhodamine 6G solution in D.I. water by casting the gel in a test tube(o.d.=13 mm and length ˜25 mm) with an aluminum foil electrode insertedalong the central axis. Chicken breast was chosen as a representativetissue to demonstrate iontophoretic delivery in accordance with oneembodiment of the present delivery system. A cylindrical core wasremoved from the center of the tissue sample to produce a drug reservoirof o.d.=15 mm. The soft-gel electrode was then placed in the reservoirinside the tissue sample and the source electrode (anode, in this case)was hooked to a DC power source with an alligator clip. The tissuesample was immersed in a beaker containing deionized water. The cathode,a regular aluminum foil electrode without gel, was placed in the PBSbeside the tissue sample and hooked up to the DC power source. In thenegative control, passive diffusion of the dye into the tissue wasallowed without any passage of current for 30 minutes. In theexperimental condition, a constant current of 10 mA (voltage ˜1.4 V) wasdriven through the electrodes for the same duration (30 minutes). Tocharacterize the extent of iontophoretic transport, cross-sections ofthe tissue sample were taken every 0.5 cm along the depth of the sample,as shown in FIG. 21. The radial transport of the dye from the edge ofthe drug reservoir was quantified. As shown in the top row of FIG. 21,in the negative control (0 mA), the dye was localized to the inner wallof the reservoir. As shown in the bottom row of FIG. 21, in theexperimental condition (10 mA), the dye spread in a radial directioninto the tissue to a distance of ˜5 mm from the edge of the reservoir.

Example 6 Delivery of Dye into Adipose Tissue (Bovine)

Bovine fat was chosen as another representative tissue to demonstrateiontophoretic delivery. A cylindrical core was removed from the centerof the tissue sample to produce a drug reservoir of o.d.=15 mm. Asoft-gel electrode similar to the one described earlier, but withplatinum foil (0.5 mm thick) as the source electrode, was then placed inthe reservoir at the center of the tissue sample and was hooked to a DCpower source with an alligator clip. The tissue sample was immersed in abeaker containing deionized water (mimicking filling the peritonealcavity). A silver chloride electrode directly inserted into the tissuesample served as the cathode and was hooked up to the DC power source.In the negative control, passive diffusion of the dye into the fattissue was allowed without any passage of current for 30 minutes. In theexperimental condition, a constant voltage of 20 V was applied betweenthe electrodes for the same duration (30 minutes). The current wasallowed to increase from 5-15 mA to maintain constant potentialdifference. To characterize the extent of iontophoretic diffusion,cross-sections of the tissue sample were taken every 0.5 cm along thedepth of the sample. The radial diffusion of the dye from the edge ofthe drug reservoir was quantified. In the negative control (0 V) dye waslocalized to the inner wall of the reservoir (not shown). In theexperimental condition (20 V), a maximum penetration depth of ˜8 mm fromthe edge of the reservoir was achieved, as shown in FIG. 22.

Example 7 Placement of Counter Electrodes for Control Over TargetedDelivery to Specific In Vivo Locations

As described previously, the position of the counter electrode may bemanipulated to exert control over targeted delivery to specific in vivolocations. In this example, two possible configurations are illustratedin FIGS. 23A and 23B, which correspond to the configuration of FIGS. 13Aand 13B, respectively. In the first configuration, the counter electrodewas placed in direct point contact with the outside surface of theagarose gel phantom. In the second configuration, the counter electrodewas wrapped around the mid-section of the gel, as shown in FIG. 23B. Theagarose phantoms were the same as those used in Example 1, and aconstant current of 5 mA was allowed to flow through the electrodes for10 minutes. In the first configuration, highly directional diffusion wasseen on the side of the agarose phantom with direct counter electrodecontact, as shown in FIG. 23A. In the second configuration, a broaderdiffusion band is seen around the midsection, demonstrating greaterdiffusivity towards the counter electrode wrapped around the phantom.

Example 8 Delivery of Dye Using Reverse Iontophoresis

The ability to extract a small molecule from the surrounding medium(like filling the peritoneal cavity) into a reservoir located inside anagarose phantom was demonstrated by employing the principle of reverseiontophoresis. To allow diffusion from the outside surface of the gel tothe central reservoir, the phantom was placed in a solution of Rhodamine6G in deionized water. For this application, the polarity of theelectrodes was switched, with the counter electrode being placed in thecentral drug reservoir, while the source electrode was placed in the dyesolution outside the gel, as shown in FIG. 24A. The electrodes were thenhooked to a DC power source with an alligator clip. In the negativecontrol, the gel was soaked in the dye solution without any passage ofcurrent for 10 minutes. In the experimental condition, a constantcurrent of 5 mA (voltage ˜9.5V) was driven through the electrodes forthe same duration (10 minutes). To characterize the extent of reverseiontophoretic diffusion, cross-sections of the agarose phantom weretaken every 0.5 cm along the length. The radial diffusion of the dyefrom the outside surface of the gel to the inside edge of the centralreservoir was quantified. In the negative control (0 mA) dye waslocalized to the outer wall of the gel, as shown in the top row of FIG.24B. In the experimental condition (5 mA) the dye spread radially towardthe central reservoir and collected there, as shown in the bottom row ofFIG. 24B. In the experimental condition, the total volume of dyeaccumulated in 10 minutes was sufficient to fill up a 3 mL glass vial,as shown in the bottom vial of FIG. 24B. This example demonstrates thepotential of the invention for delivering drug molecules from theoutside surface of an organ to the inner core. It also demonstrates anapplication requiring the extraction of a toxin from the target tissueinto a central reservoir from which it can be safely and easilyextracted.

Example 9 Variable Delivery of Rhodamine 6G Dye into Agarose PhantomsUsing Independently Controlled Electrodes

An assembly of two independently-powered, insulated electrodes wasdeveloped to demonstrate variable controlled delivery, as describedpreviously. By allowing independent control over parameters foriontophoretic delivery such as current, voltage and time, we were ableto demonstrate variable delivery zones at two distinct sites within thesame lumen. Two insulated aluminum foil electrodes similar to the oneshown in Example 3 above, were combined into a single assembly accordingto the schematic shown in FIG. 5. The insulated double-electrodeassembly was immersed in the central reservoir of an agarose phantom (2%agarose w/v in deionized water). A solution of 0.5% Rhodamine 6G in D.I.water was used to model the delivery of a small molecule drug and wasfilled inside the cored reservoir in the agarose phantom. The agarosephantom was immersed in a beaker containing 0.25×PBS solution. A pair ofbare aluminum foil electrodes served as cathodes, and were placed in thePBS beside the phantom. Both sets of electrodes were hooked to twoindependent DC power sources with alligator clips. In the negativecontrol, passive diffusion of the dye was allowed without any passage ofcurrent for 5 minutes. In the experimental condition, one electrode wasset for a constant current of 5 mA, while the other was operated at aconstant voltage of 20 V. Duration of delivery was held constant at 5minutes, but as noted earlier, all of the above parameters can beindependently controlled. To characterize the extent of iontophoreticdiffusion, the agarose phantom was sectioned longitudinally. Under UVlight, a difference is seen in the extent of diffusion from the sectionsof the phantom exposed to the uninsulated sections of both electrodes inthe assembly, as shown in FIG. 25. For example, the bottom electrodeshows uniform diffusion at the bottom of the well, whereas theuninsulated section of the top electrode shows more diffusion on thebare (anterior) side as opposed to the insulated (posterior) side. Thisexample demonstrates that a similar electrode assembly can be used tocontrol the location and extent of delivery at multiple proximal siteswithin the same lumen or its branches. This may be particularly usefulin targeted delivery to metastatic tumors within the same organ that canbe accessed through a common ductal or vascular network.

Example 10 Variable Delivery of Rhodamine 6G Dye into Agarose PhantomsUsing Independently Controlled Electrodes with Built-in Drug Reservoir

A variation of the double-electrode assembly previously described inExample 9 was developed with a built-in drug reservoir. The insulateddouble-electrode assembly was immersed in a test-tube of 2% agarose gelcontaining a 5 mg aqueous solution of Rhodamine 6G. The soft-gelelectrode assembly was then inserted into an 2% agarose phantom having acored out central cavity (diameter: 1.5 mm). The agarose phantom wasimmersed in a beaker containing 0.25×PBS solution, as shown in FIG. 26A.Two bare aluminum foil electrodes served as cathodes, and were placed inthe PBS beside the phantom. Both sets of electrodes were hooked to twoindependent DC power sources with alligator clips. In the negativecontrol, passive diffusion of the dye was allowed without any passage ofcurrent for 7 minutes. To demonstrate independent control of bothelectrodes, one electrode was set for a constant current of 5 mA for 5minutes, while the other was operated at a constant current of 15 mA for7 minutes. To characterize the extent of iontophoretic diffusion, theagarose phantom was sectioned longitudinally. Under UV light, adifference is seen in the extent of diffusion from the sections of thephantom exposed to the uninsulated sections of both electrodes in theassembly, as shown in FIG. 26B. Depletion of the dye is seen from theareas of the gel exposed to uninsulated tips of the electrodes.Furthermore, two distinct delivery zones can be seen resulting from thetwo independently controlled electrodes.

Example 11 Delivery of Doxorubicin into Agarose Phantoms

A cylindrical tube of 2% (w/v) agarose gel in deionized (D.I.) water wasfabricated as a phantom with an outer diameter (o.d.)=2.5 cm and length˜3-4 cm. A concentric reservoir for holding the dye (o.d=0.8 cm, length˜2 cm) was cored out from the top surface along the longitudinal axis ofthe gel cylinder. Electrodes were fabricated out of platinum foil (width˜0.25 cm, length ˜3 cm, thickness ˜0.05 cm). A solution of 0.25%Doxorubicin in 4.875% DMSO and 94.875% DI water was used to model thedelivery of a small molecule drug. The dye was filled inside the coredreservoir in the agarose phantom and the source electrode (anode, inthis case) was inserted into the dye reservoir. The other end of theanode was hooked to a DC power source with an alligator clip. Theagarose phantom was immersed in a beaker containing DI water. Thecathode, a second piece of platinum foil, was placed in the PBS besidethe agarose phantom and hooked up to the DC power source. In thenegative control, passive diffusion of the dye was allowed without anypassage of current for 5 minutes. In the experimental condition, aconstant current of 5 mA (voltage ˜9.5V) was driven through theelectrodes for the same duration (5 minutes). As shown in FIG. 27, tocharacterize the extent of iontophoretic diffusion, cross-sections ofthe agarose phantom were taken every 0.5 cm along the length. The radialdiffusion of the dye from the edge of the cored reservoir wasquantified. In the negative control (0 mA) dye was localized to theinner wall of the reservoir (bottom row), while in the experimentalcondition (5 mA) the dye spread radially to the edge of the agarosephantom (top row).

Example 12 Injection of Rhodamine 6G into Pancreatic Duct and Placementof Electrodes on Outer Surface of Pancreas

As shown in FIG. 28A, Liquified 2% (w/v) agarose gel containing 0.5%Rhodamine 6G solution in D.I. water was injected into the pancreas ductthrough a 18G IV catheter, where it solidified upon contact. The sourceelectrode, made of aluminum foil, was placed on one side of thepancreas, and the counter electrode, made of aluminum foil, was placedon the opposite side of the pancreas. The electrodes were hooked to a DCpower source with alligator clips. The tissue sample was immersed in abeaker of DI water. In the experimental condition, a constant current of5 mA (voltage ˜2.4 V) was driven through the electrodes for the sameduration (30 minutes). To characterize the extent of iontophoreticdiffusion, cross-sections of the tissue sample were taken every 0.5 cmalong the depth of the sample, as shown in FIG. 28B. The radialdiffusion of the dye from the edge of the drug reservoir was quantified.In the experimental condition (5 mA), the dye spread in a radialdirection into the tissue to a distance of ˜3 mm from the edge of thereservoir.

Example 13 Delivery of Dye into Pancreas Using Flat Electrodes

A soft-gel source electrode was fabricated from Liquified 2% (w/v)agarose gel containing 0.5% Rhodamine 6G solution in D.I. water bycasting the gel in a Petri dish with an aluminum foil electrode insertedon top of gel. The source electrode was placed on one side of thepancreas, and the counter electrode was placed on the opposite side ofthe pancreas. The electrodes were hooked to a DC power source withalligator clips. The tissue sample was immersed in a beaker of DI water.In the experimental condition, a constant current of 5 mA (voltage ˜2.4V) was driven through the electrodes for the same duration (30 minutes).As shown in FIG. 29, in the experimental condition (5 mA), the dye movedfrom the agarose source electrode into the tissue.

Example 14 Delivery of Dye Through Pancreatic Duct Using Probe Electrode

A soft-gel source electrode was fabricated from Liquified 2% (w/v)agarose gel containing 0.5% Rhodamine 6G solution in D.I. water bycasting the gel in a test tube (o.d.=5 mm and length ˜25 mm) withplatinum wire inserted along the central axis. The soft-gel sourceelectrode was probed into the pancreatic duct, and the counterelectrode, made of platinum foil, was placed on the outer surface of thepancreas, as shown in FIG. 30A. The electrodes were hooked to a DC powersource with alligator clips. The tissue sample was immersed in a beakerof DI water. In the negative control, passive diffusion of the dye intothe tissue was allowed without any passage of current for 30 minutes. Inthe experimental condition, a constant current of 20 mA (voltage ˜9.2 V)was driven through the electrodes for 30 minutes. To characterize theextent of iontophoretic diffusion, cross-sections of the tissue samplewas taken every 1 cm along the depth of the sample. As shown in FIG.30B, in the experimental condition (20 mA), the dye moved from theagarose source electrode into the tissue. As shown in FIG. 30C, in thenegative control (0 mA), the dye was localized to the inner wall of thepancreatic duct. In the experimental condition (20 mA), the dye spreadin a radial direction into the tissue to a distance of ˜3 mm from theedge of the reservoir.

Example 15 Delivery of PRINT® Nanoparticles into Agarose Phantoms

A miniaturized agarose phantom was used to demonstrate the delivery ofPRINT® nanoparticles using iontophoresis. A 2% agarose gel was pouredinto a small test tube (diameter 13 mm) and a capillary tube (o.d. 1 mm)was used to create a central reservoir. An aqueous solution offluorescent polyampholyte PRINT® nanoparticles (size: 343 nm, charge:˜59 mV, concentration: 9.5 mg/mL) was deposited into the reservoir. Aplatinum wire (diameter 0.25 mm) was inserted into the reservoir asanode and a similar wire served as a cathode outside the phantom. Thephantom was then immersed in a solution of 0.25×PBS, and the electrodeswere hooked up to a DC power source using alligator clips. In thenegative control, the particles were allowed to passively diffuse intothe gel without the application of current for 5 minutes. Foriontophoretic delivery, the nanoparticles were driven into the gel by aconstant current of 5 mA for the same duration. The phantoms were thencut into 1 mm thick transverse slices that were placed onto glass slidesfor imaging under a fluorescent microscope. The difference in the extentof migration due to the electric field is shown in FIGS. 31A and 31B.FIG. 31A represents passive diffusion, while FIG. 31B shows results frommigration in the 5 mA current.

The following examples, which are not meant to be limiting, generallyrelate to proof-of-concept studies relating to electric field assisteddelivery (EFAD), engineering of EFAD devices, exploratory studies inlarge animals have been performed, and methods of pharmacokineticanalysis for local delivery mechanisms have been developed.Proof-of-concept studies for EFAD were performed in tumor tissuesurrogates and pancreatic tumor tissue. Two EFAD devices were designedand prototyped for different approaches to the primary pancreatic tumor,including endoductal, and surgically implantable. Four large animalmodels were evaluated for the different device approaches, and thecanine model was chosen as the most amenable to all device approaches. Atissue sampling system and methods of pharmacokinetic analysis fortissue and plasma have also been developed. Overall, these devices couldpotentially offer an entirely new modality for the treatment ofpancreatic cancer under the emerging field of interventional oncology.Moreover, the further development of these devices could translatedirectly into new treatments for other types of primary tumors andmetastatic diseases.

Example 16 Examination of Gemcitabine Transport in Pancreatic Tissue andTumor Tissue

To assess and optimize the electrical transport parameters in tissue, atransport testing system was built (see FIG. 32A). The transport ofgemcitabine, the current standard-of-care therapy for pancreatic cancer,was evaluated in orthotopic xenograft tumors using this transporttesting system (see FIG. 32B). The tumors chosen for the studies were1.25 to 1.5 cm in diameter because of compatibility with the size of thetransport cell. The gemcitabine was used according to the currentclinical formulation (Gemzar® to Eli Lilly and Company), at aconcentration relevant to that administered in the clinic. For threetumors, a constant current of 20 mA was applied for 20 minutes, and theamount of gemcitabine was evaluated using a high-performance liquidchromatography (HPLC) analysis method. For three additional tumors, nocurrent was applied, which allowed for passive diffusion of thegemcitabine into the tumor, and the amount of gemcitabine was evaluatedusing the same HPLC analysis method. As shown in FIG. 32B, an eight-foldincrease in the amount of gemcitabine was measured within an orthotopicxenograft tumor when a constant current of 20 mA was applied for 20minutes compared to the control (no current applied).

Example 17 Implantable Device

The laparoscopic implantable device was developed for surgicalimplantation onto the surface of the pancreas in proximity to the tumor.The device would be sutured or bioadhered to the pancreas. As seen inFIGS. 33A-D, the laparoscopic implantable system was designed with adrug reservoir, cellulose membrane, polyurethane shell, AgCl electrode,conducting wire, and an inlet and outlet for drug flow into and out ofthe reservoir. The reservoir is covered by a semi-permeable membranethrough which drug can be transported. Drug flows through an inlet tubeand is removed from the reservoir through an outlet tube. A metallicelectrode is situated at the back of the reservoir. A conducting wire issituated through the reservoir to connect to the metallic electrode.There exist anchor points on the device situated for attachment totissue. The reservoir and flow system allow for a constant drugconcentration around the electrode and the removal of the by-products ofthe redox reaction. The cellulose membrane will minimize uncontrolleddrug flow out of the system.

Example 18 Studies in Large Animals

As there are no readily available large animal models of pancreaticcancer, device development and evaluation will be performed in healthylarge animals. Four large animal models, including goats, sheep, dogs,and pigs, were evaluated for three device approaches to the pancreas.Table 1 shows the relative assessment of each animal model. The dog wasdetermined to be the most amenable to all device approaches.

TABLE 1 Assessment of animal model for device approach. Animal SurgicalEndoscopic Intravascular Goat 2 2 5 Sheep 2 2 5 Dog 4 4 4 Pig 2 2 4Scale: (1) Not feasible-(5) Very feasible

The reservoir based system similar to that shown in FIGS. 33A-D wassurgically implanted onto the pancreas of a canine. All animal modelswere anesthetized and attached to a respirator for the entirety of thestudy. The implantable device approach was assessed via a laparotomy.The pancreas was assessed for ease of access.

There were three arms for the large animal experiment: 1. Device withcurrent; 2. Device without current; and 3. IV Infusion (see Table 2).The device was sutured onto the right lobe of the canine pancreas.Gemcitabine formulated at clinically relevant concentrations was pumpedinto and out of the device at ˜1.5 mL/min during the application of 10mA of current applied for 60 minutes. Control experiments were runwithout current. After administration of therapy, the pancreas wasexcised and snap frozen for analysis. The gemcitabine was measured fromthe section tissue using UV-HPLC from established protocols in theliterature (see Olive, K P, et al. Science 324 (2009) 1457-1461 andKirstein M N, et al., J Chromatogr B Analyt Technol Biomed Life Sci. 835(2006) 136-142). Shown in FIG. 34 are the results obtained from thethree experimental arms analyzing the mass of gemcitabine from theentire pancreas.

TABLE 2 Experimental arm parameters Device Device w/o w/Current CurrentIV Infusion Current 10 mA 0 mA — Time of 60 minutes 60 minutes 30minutes Administration Sample Size 5 5 4

In FIG. 35, the transport distance of the gemcitabine is shown for thewith and without current arms. In particular, FIG. 35 shows thequantification of gemcitabine mass at different distances away from theelectrode. The plasma concentrations determined for the with and withoutcurrent arms are given in Table 3. Plasma concentrations of gemcitabinewere detected at 15-minute increments prior to and during the largeanimal study. The tissue was sectioned using a cryostat microtome andgemcitabine was extracted using an established extraction method (seeOlive et al.). The gemcitabine was detected and quantified using UV-HPLC(see Olive et al. and Kirstein et al.). Essentially, the gemcitabinelevels detected in the plasma of the dogs was below the detectablelimit.

TABLE 3 Plasma Concentrations of Gemcitabine. Device - Current AppliedDevice - No Current Sample Gem Concentration (ug/mL) Gem Concentration(ug/mL) −15 min  * *  0 min * * 15 min * * 30 min * * 45 min * * 60min * * * Below limit of detection

Pharmacokinetics and Analysis in Tissue and Serum

The pharmacokinetic analysis for tissue and serum has been developedaccording to a method developed by Kirstein et al. A validated standardcurve has been developed and will be used for future in vivo studies(data not shown).

Example 19 Endoductal Device

A second device approach developed for the treatment of pancreaticcancer was an endoductal device. The device was modeled in a 3D CADprogram (SolidWorks® to Dassault Systemes SolidWorks Corporation) priorto prototyping. The endoductal approach was developed according toendoscopic retrograde cholangiopancreatography (ERCP) devices, which usea duodenoscope to access the major duodenal papilla. A double ballooncatheter was designed, as seen in FIG. 36. A multi-luminal tube was usedfor independent control of balloons, drug expulsion, and electricalcontact with the electrode. The catheter contains two independentlycontrolled balloons that sandwich an electrode. The balloons andelectrode are UV-cured to the tube. A guide wire is attached to thefront end of the device. Drug can be expelled from the device around theelectrode and would fill the cavity between the two independentlycontrolled balloons. A conducting wire is in contact with the silverelectrode.

The tubing of the catheter contained four lumens for saline, drug, and aconducting wire (see FIG. 37). The two identical lumens were used toinflate the balloons with saline, the small lumens were used for theconducting wire, and the larger lumen was used for the transport ofdrug. FIG. 37 illustrates exemplary dimensions for the catheter andlumens according to one experimental implementation and is not meant tobe limiting. A nitinol conducting wire was connected to a silverelectrode located between two pre-fashioned urethane balloons. Thedouble balloon catheter system created a reservoir for drug containment,which could limit drug exposure to the epithelium; allow for goodelectrical contact between the electrode and drug, and reduce the effectof extraneous ions in the system. Ultimately, an endoductal EFAD devicecould be designed to slip over a guide wire that has entered the mainpancreatic duct.

1. A delivery system for local drug delivery to a target site ofinternal body tissue, comprising: a source electrode adapted to bepositioned proximate to a target site of internal body tissue; a counterelectrode in electrical communication with the source electrode, thecounter electrode being configured to cooperate with the sourceelectrode to form a localized electric field proximate to the targetsite; and a reservoir capable of interacting with the localized electricfield, the reservoir being configured to carry a cargo capable of beingdelivered to the target site when exposed to the localized electricfield formed between the source electrode and the counter electrode. 2.A delivery system according to claim 1, further comprising an electrodedeployment device configured to insert at least one of the sourceelectrode and the counter electrode proximate to the target site ofinternal body tissue in vivo.
 3. A delivery system according to claim 2further comprising a control system in communication with the electrodedeployment device, the control system being configured to guide theelectrode deployment device with placement of the source electrode andthe counter electrode.
 4. (canceled)
 5. A delivery system according toclaim 2 wherein the electrode deployment device comprises a first andsecond expandable member serially disposed along a longitudinal axis ofthe catheter device, the source electrode being axially disposed betweenthe first and second expandable members such that, upon inflation of thefirst and second expandable members to occlude the target site, thetarget site is isolated and the delivery of the cargo is contained tothe target site.
 6. A delivery system according to claim 2 wherein theelectrode deployment device comprises a perforated polymer sheath, thecargo being capable of exiting the catheter device through a pluralityof perforations defined by the perforated polymer sheath, and the sourceelectrode comprising an array of probes terminating at different lengthsand being independently powered such that the probes are capable ofbeing variably controlled, the source electrode further comprising aplurality of insulating members disposed about and between the probes soas to form cargo delivery zones substantially aligned with theperforations of the perforated polymer sheath.
 7. A delivery systemaccording to claim 2 wherein the electrode deployment device comprises aproximal end and a distal end having the source electrode disposedthereabout for positioning proximate to the target site, the sourceelectrode comprising a hollow needle member forming the reservoir, theproximal end having a port to fluidly connect the proximal and distalends such that the reservoir is capable of being remotely filled withthe cargo.
 8. A delivery system according to claim 1 wherein the cargocomprises at least one of small ionic molecules, nucleic acids,proteins, organic nanoparticles, therapeutic agents, and imaging agents.9. A delivery system according to claim 1 wherein the source electrodeincludes an array of probes comprising one of thin wires, foil, mesh,pellets, disks, stents, clamps, prongs, clips, needles, hollow tubes,and combinations thereof.
 10. (canceled)
 11. A delivery system accordingto claim 1 further comprising at least one insulating member at leastpartially disposed about the source electrode, the at least oneinsulating member being configured to confer directionality to thetransport profile of the cargo released from the reservoir.
 12. Adelivery system according to claim 1 wherein the source electrodecomprises an array of probes, at least one of the probes comprising animaging device such that the source electrode is capable of being imagedfor positioning thereof proximate to the target site.
 13. A deliverysystem according to claim 1 wherein the counter electrode includes anion selective membrane disposed at least partially thereabout forlimiting interference of non-cargo ions with the cargo to be deliveredto the target site.
 14. A delivery system according to claim 1 furthercomprising a coolant device operably engaged with the counter electrode,the coolant device being configured to provide cooling to the counterelectrode during use thereof to form the electric field.
 15. A deliverysystem according to claim 1 wherein the reservoir is comprised of apolymer matrix at least partially encapsulating the source electrode,the polymer matrix incorporating the cargo therein such that uponactivation of the electric field the cargo diffuses out of the polymermatrix and toward the counter electrode.
 16. A delivery system accordingto claim 13 wherein the source electrode includes at least oneinsulating member at least partially disposed thereabout such that thepolymer matrix further encapsulates the at least one insulating member,the at least one insulating member being configured to conferdirectionality to the transport profile of the cargo released from thereservoir.
 17. A delivery system according to claim 13 wherein thesource electrode comprises an array of probes terminating at differentlengths and being independently powered such that the probes are capableof being variably controlled, the source electrode further comprising aplurality of insulating members disposed about and between the probes soas to form cargo delivery zones.
 18. (canceled)
 19. (canceled)
 20. Adelivery system according to claim 1 wherein the reservoir is remotelydisposed from the source electrode, the reservoir and the sourceelectrode being in fluid communication via a hollow conduit member tofacilitate transfer of the cargo from the reservoir proximate to thesource electrode.
 21. (canceled)
 22. A delivery system according toclaim 1 wherein the reservoir comprises a patch member impregnated withthe cargo, the patch member being adapted for implantation proximate tothe target site.
 23. (canceled)
 24. A delivery system according to claim1 wherein the source electrode and the counter electrode each comprisesa patch member, the patch member of the source electrode having thecargo incorporated therein.
 25. (canceled)
 26. A method of delivering acargo to a target site of internal body tissue, the method comprising:disposing a source electrode proximate to a target site of internal bodytissue in vivo; disposing a counter electrode in electricalcommunication with the source electrode, the counter electrode beingconfigured to cooperate with the source electrode to form a localizedelectric field proximate to the target site; disposing a reservoir suchthat the reservoir is capable of interacting with the localized electricfield, the reservoir being configured to carry a cargo capable of beingdelivered to the target site when exposed to the localized electricfield formed between the source electrode and the counter electrode; andapplying a voltage potential across the source and counter electrodes toform an electric field, thereby delivering at least a portion of thecargo to the target site. 27-53. (canceled)